At least eight progressive neurodegenerative disorders are caused by an expansion of the naturally occurring CAG tract that encodes a polyglutamine (polyQ) repeat within the corresponding protein. These diseases include Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA; also known as Kennedy's disease), dentatorubral-pallidoluysian atrophy, spinocerebellar ataxia type 1 (SCA1), SCA2, SCA6, SCA7, and Machado-Joseph disease (MJD/SCA3)(Reddy et al., Trends Neurosci. 22:248-255, 1999). With the exception of SCA6 (CACNL1A4; Zhuchenko et al., Nature 15:62-69, 1997), which is characterized by a minimal repeat expansion, affected individuals typically show a similar range of repeat expansion above ˜35 repeats (Kakizuka et al., Trends Genet. 14:396-402, 1998).
Of the diseases listed above, HD has arguably been studied the most intensely, and one of the tools extensively used in those studies is a transgenic mouse model. The neurons within mice transgenic for exon 1 of huntingtin are marked by intranuclear inclusions that contain huntingtin and ubiquitin (Bates et al., Brain Pathol. 8:699-714, 1998; and Paulson et al., Am. J. Hum. Genet. 64:339-345, 1999). These inclusions indicate that protein misfolding and aggregation mediate neuronal pathogenesis (Davies et al., Cell 90:537-548, 1997). Moreover, nuclear inclusions have been observed in the affected regions of brains of patients diagnosed as having a polyQ-associated disease (Kakizuka et al., Trends Genet. 14:396-402, 1998; DiFiglia et al., Science 277:1990-1993, 1997; Bates et al., Brain Pathol. 8:699-714, 1998; and Paulson et al., Am. J. Hum. Genet. 64:339-345, 1999).